Prostaglandin B{HD 3 {B analogs

ABSTRACT

This disclosure relates to prostaglandins of the PG3 series including PGE3, PGF3 , PGF3 , PGA3, and PGB3, to various analogs of those in racemic form, and to novel processes for making those. This disclosure also relates to certain fluorine and alkyl substituted analogs and certain acetylenic analogs of PGE3, PGF3, PGF3 , PGA3, and PGB3 in both racemic and optically active form, and to processes for making those. These various analogs are useful for the same pharmacological purposes as the known optically active forms of PGE3, PGF3 , PGF3 , PGA3, and PGB3, including anti-ulcer, inhibition of platelet aggregation, increase of nasal patency, labor inducement, fertility control, and wound healing.

United States Patent Axen May 13, 1975 PROSTAGLANDIN B ANALOGS [56] References Cited [75] Inventor: Udo F. Axen, Comstock, Mich. FOREIGN PATENTS OR CATIONS Assignee: The pj p y Kalamazoo 2,l [8,686 ll/l97l Germany 260/468 h. MIC Primary Examiner-Robert Gerstl [22] Filed: Nov. 5, 1973 [2i] Appl. No.: 412,986 [571 ABSTRACT This disclosure relates to prostaglandins of the PG; se- Related [1.8. Application Data fies includin g PGEgg, pGFg PGFgB, PGA3, and cominuaticm-in-pafl of H2932, f- P08 to various analogs of those in racemic form,

P 3775-462 whch a and to novel processes for making those This discloggg g g of 30312 sure also relates to certain fluorine and alkyl substia an one tuted analogs and certain acetylenic analogs of PGE 52 u 5 Cl 260/468 0- 260/211 R- 260/247 2 R- and both racemic 6 5 6 R4 260/29'3 65' 26O/326 3, f and optically active form. and to processes for making 260mm 260/4lO 9 f 260MB. those These various analogs are useful for the same harmacological purposes as the known optically ac- 260 429.9; 260 439 R; 260 448 R; 2605/0] 260/501 W tive forms of PGE PGF, For Pom. and

' 260/561 260/514 PGB including anti-ulcer, inhibition of platelet aggre- Int Cl C(nc 6k 69/74 gation, increase of nasal patency, labor inducement, Fie'ld l l l l l l l l l l llllll 260/468 D 514 D fertility control, and wound healing 23 Claims, No Drawings PROSTAGLANDIN B3 ANALOGS CROSS REFERENCE TO RELATED APPLICATION This application is a continuation-in-part of copending application Ser. No. 112,032, filed Feb. 2, 1971, now US. Pat. No. 3,775,462 which is a continuationin-part of copending application Ser. No. 30,312, filed Apr. 20, 1970, and now abandoned.

BRIEF DESCRIPTION OF THE INVENTION This invention relates to compositions of matter, and to methods and intermediates for producing them. In particular, the several aspects of this invention relate to racemic prostaglandin E (PGE racemic prostaglandin F (PGF and POP- p racemic prostaglandin A (PGA prostaglandin E (PGB- to the corresponding acetylenic prostaglandins, 5,6,17,18- dehydro-PGE 5,6,l7,l8-dehydro-PGF 5,6,17,18- dehydro-PGF- p 5,6,l7,18-dehydro-PGA and 5,6,l7,l8-dehydro-PGB to analogs of those prostaglandins and 5,6,17, l S-dehydro-prostaglandins; to processes for producing racemic PGE POE P61 PGA- PGB the corresponding 5,6,17,18-dehydroprostaglandins, and the analogs thereof; to processes for resolving the racemates into the dand 1- forms; and to chemical intermediates useful in those methods.

Optically active PGE (the natural or (1- configuration) is a known substance. Bergstrom, Science 157, 382 (1967); Samuelson, .1. Amer. Chem. Soc., 85, 1878 (1963). Optically active PGF (a and ,8), obtained by the borohydride reduction of optically active PGE is also a known substance; Samuelson, biochemica Biophysica Acta, 84, 707 (1964); so also is optically active PGA British Pat. No. 1,097,533. Optically active PGE optically active POI- and optically active PGF p are also disclosed in British Pat. No. 1,040,544.

The prior art methods for producing prostaglandins are costly and difficult, the necessary biological materials are limited, and the methods are not adaptable to production of a wide variety of prostaglandin intermediates and the analogs.

It is the purpose of this invention to provide processes for the production of compounds with prostaglandinlike activity in substantial amounts and at reasonable cost. The useful compounds produced according to the processes of this invention comprise racemic P GE racemic PGF racemic PGF p racemic PGA racemic PGB the corresponding 5,6,17,18- dehydro-prostaglandins, and other hitherto unavailable racemic and optically acitve analogs thereof such as the enantiomorphs (dand 1- forms) of P and the 5,6,1 7,1 8 deydro compounds.

PGE has the following structure:

PGFH.X has the following structure:

The above formulas represent the natural configuration. Racemic PGE PGF a PGF p PGA and P68 are each represented by the combination of one of the above formulas and the mirror image (enantiomorph) of that formula. See Nature, 212, 38 1966) for discussion of the stereochemistry of the prostaglandins.

ln formulas 1,11, III, IV, and V, as well as in the formulas given hereinafter, broken line attachments to the cyclopentane ring indicate substituents in alpha configuration, i.e., below the plane of the cyclopentane ring. Heavy solid line attachments to the cyclopentane ring indicate substituents in beta configuration, i.e., above the plane of the cyclopentane ring.

PGE PGF ,PGF;,p PGA and PGB are derivatives of prostanoic acid which has the following structure and atom numbering:

COOP "I 6 5W 3 4 a 16 17 18 i9 0 \ii A systematic name for prostanoic acid is 7-[(2B-octyl)- cyclopent-loz-yU] heptanoic acid.

Compounds similar to formula VI but with carboxylterminated side chains attached to the cyclopentane ring in beta configuration are designated 8-isoprostanoic acids, and have the following formula:

COOH

A systematic name for iso-prostanoic acid is 7-[(2B- octyll-cyclopent-lB-yU] heptanoic acid.

Prostaglandin E and its analogs and isomers produced according to the processes of this invention are represented by the formula:

wherein R, is hydrogen, alkyl of one to 8 carbon atoms, inclusive, cycloalkyl of 3 to 10 carbon atoms, inclusive, aralkyl of 7 to 12 carbon atoms, inclusive, phenyl, phenyl substituted with one to 3 chloro or alkyl of one to 4 carbon atoms, inclusive, or ethyl substituted in the B-position with 3 chloro, 2 or 3 bromo, or l, 2, or 3 iodo; wherein R is alkyl of one to 4 carbon atoms, inclusive, substituted with zero to 3 fluoro; wherein R and R are hydrogen or alkyl of one to 4 carbon atoms, inclusive; wherein n is an integer of one to 4, inclusive; wherein A is alkylene of one to 10 carbon atoms, inclusive, substituted with zero to 2 fluoro, and with one to 5 Carbon atoms, inclusive, between -COOR, and

and pharmacologically acceptable salts thereof wherein R, is hydrogen.

Prostaglandin F and its analogs and isomers produced according to the processes of this invention are represented by the formula:

wherein R R R;,, R,, and A are as defined above for S formula Vllle, and pharmacologically acceptable salts thereof when R is hydrogen.

Prostaglandin A and its analogs and isomers pro duced according to the processes of this invention are represented by the formula:

wherein R R R R and A are as defined above for formula VIlIe, and the pharmacologically acceptable salts thereof wherein R is hydrogen.

Prostaglandin B and its analogs and isomers (including its enantiomorphs) produced according to the processes of this invention are represented by the formula:

wherein R R R R and A are defined above for formula Vllle, and pharmacologically acceptable salts thereof wherein R is hydrogen.

The wavy line, as used above, and elsewhere herein, includes both configurations, i.e., alpha and beta, or endo or exo. The word *racemic indicates an equal mixture of a compound of the formula shown, which is the natural configuration, and its enantiomorph.

Compounds of formula Vllle, lXe, Xe, and Xle have their counterpart where the cis-ethylenes are dehydro, i.e., ethynylene. These dehydro analogs here designated as Vllld, IXd, X0, and Xld, are intermediates, as will be shown, for making the compounds of formulas Vllle, lXe, and Xle. Racemic dehydro compounds give racemic final products. An enantiomorph of the dehydro compound (the configuration as shown or the mirror image thereof) gives the corresponding enantiomorph of the final compound.

Also included in formulas Vlll, IX, X, and X] are separate isomers wherein the side chain hydroxy is in R or S configuration. All of the compounds encompassed by formulas Vlll, IX, and X have the trans CH=C- R -CR OH side chain attached in beta configuration,

Formulas Vllle, lXe, Xe, and XIe represent PGE PGF PGA and PGB respectively, when in these formulas R R and R, are each hydrogen, )1 is 1, R, is ethyl, A is trimethylene, the attachment of CH- CH=CH-A--COOR to the cyclopentane ring is in alpha configuration, and the configuration of the side chain hydroxy is S.

With regard to formulas Vlll to Xl, inclusive, examples of alkyl of one to 4 carbon atoms, inclusive, are methyl, ethyl, propyl, butyl, and isomeric forms thereof. Examples of alkyl of one to 8 carbon atoms, inclusive, are those given above, and pentyl, hexyl, heptyl, octyl, and isomeric forms thereof. Examples of alkyl of one to l0 carbon atoms, inclusive, are those given above, and nonyl, decyl, and isomeric forms thereof. Examples of cycloalkyl of 3 to l0 carbon atoms, inclusive, which includes alkyl-substituted Cycloalkyl, are cyclopropyl, Z-methylcyclopropyl, 2,Z-dimethylcyclopropyl, 2,3-diethylcyclopropyl, 2-butylcyclopropyl, cyclobutyl, Z-methylcyclobutyl, 3-propylcyclobutyl. 2,3,4 triethylcyclobutyl, cyclopentyl, 2,2-dimethylcyclopentyl, 3-pentylcyclopentyl.

B-tert-butylcyclopentyl, cyclohexyl, 4-tertbutylcyclohexyl, 3-isopropylcyclohexy, 2,2-dimethylcyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl. Examples of aralkyl of 7 to 12 carbon atoms, inclusive, are benzyl, phenethyl, l-phenethyl, l-phenylethyl, Z-phenylpropyl, 4-phenylbutyl, 3- phenylbutyl, 2-( l-naphthylethyl and l-(2- naphthylmethyl). Examples of phenyl substituted by one to 3 chloro or alkyl of one to 4 carbon atoms, inclusive, are p-chlorophenyl, m-chlorophenyl, ochlorophenyl, 2,4-dichlorophenyl, 2,4,6- trichlorophenyl, p-tolyl, m-tolyl, o-tolyl, p-ethylphenyl, p-tert-butylphenyl, 2,5-dimethylphenyl, 4-chloro-2- methylphenyl, and 2,4-dichloro-3-methylphenyl.

Examples of alkylene of one to l0 carbon atoms, inclusive, are methylene, ethylene, trimethylene, tetramethylcne, pentamethylene, and isomeric branched chain forms thereof, l-, 2-, and 3- methylpentamethylene, l-, 2-, 3-ethylpentamethylene, l-, 2 and 3-propylpentamethylene, l-, 2-, and 3- butylpentamethylene, and l-, 2-, and 3-pentylpentamethylene.

Examples of alkyl of one to 4 carbon atoms, inclusive, substituted with one to 3 fluoro, are 2fluoroethyl, 2-fluorobutyl, 3-fluorobutyl, 4-fluorobutyl, 3,4- difluorobuty], 2,2,2-trifluoroethyl, and 4,4,4trifluorobutyl.

Examples of alkylene of one to carbon atoms, inclusive, substituted with one or 2 fluoro, have the formulas CH2CF2, H -CH CH CH CF CH CHCH CHF- PGE PGF ,PGF p PGA and PGB and their esters and pharmacologically acceptable salts, are extremely potent in causing various biological responses. For that reason, these compounds are useful for pharmacological purposes. See, for example, Bergstrom et al., Pharmacol. Rev. 20, l (I968), and references cited therein. A few of those biological responses are systemic arterial blood pressure lowering in the case of P65 P055 and PGA; as measured, for example, in anesthetized (pentobarbital sodium) pentoliniumtreated rats with indwelling aortic and right heart cannulas', pressor activity, similarly measured, for PGF a stimulation of smooth muscle as shown, for example, by tests on strips of guinea pig ileum, rabbit duodenum, or gerbil colon; potentiation of other smooth muscle stimulants; antilipolytic activity as shown by antagonism of epinephrine-induced mobilization of free fatty acids or inhibition of the spontaneous release of glycerol from isolated rat fat pads; inhibition of gastric secretion in the case of PGE and PGA as shown in dogs with secretion stimulated by food or histamine infusion; activity on the central nervous system; decrease of blood platelet adhesiveness as shown by platelet-toglass adhesiveness, and inhibition of blood platelet aggregation and thrombus formation induced by various physical stimuli, e.g., arterial injury, and various biochemical stimuli, e.g., ADP, ATP, serotonin, thrombin, and collagen; and in the case of PGE and PBG stimulation of epidermal proliferation and keratinization as shown when applied in culture to embryonic chick and rat skin segments.

Optically active PGE and its esters and pharmacologically acceptable salts, are also extremely potent in causing the same biological responses as PGE Horton et al., Brit. J. of Pharm. and Chemotherapy, 21, I82 (1963); Bergstrom et al., acta physiol. science, 59, 493 (1963); Heinberg et al., J. Clinic. Investigation, 43, 1533 (1964); Bergstrom et al., acta physiol. science, 60, 170 H964); and Sandberg et al., Acta Obstetrica et Gynecolojica Science, 43, (l964). Optically active PGF and PGA;, which are obtained from optically active PGE also cause the same biological responses as PGF and PGA Because of these biological responses, these known prostaglandins are useful to study, prevent, control, or alleviate a wide variety of diseases and undesirable physiological conditions in birds and mammals, including humans, useful domestic animals, pets, and zoological specimens, and in laboratory animals, for example, mice, rats, rabbits, and monkeys.

For example, these compounds, and especially PGE are useful in mammals, including man, as nasal decongestants. For this purpose, the compounds are used in a close range of about 10 pg. to about 10 mg. per mil. of a pharmacologically suitable liquid vehicle or as an aerosol spray, both for topical application. POE; is similarly useful when administered in equivalent doses.

PGE and PGA, are useful in mammals, including man and certain useful animals, e.g., dogs and pigs, to reduce and control excessive gastric secretion, thereby reducing or avoiding gastrointestinal ulcer formation, and accelerating the healing of such ulcers already present in the gastrointestinal tract. For this purpose, the compounds are injected or infused intravenously, subcutaneously, or intramuscularly in an infusion dose range about O.l ug. to about 500 pg. per kg. of body weight per minute, or in a total daily dose by injection of infusion in the range about 0.1 to about 20 mg. per kg. of body weight per day, exact dose depending on the age, weight, and condition of the patient or animal, and on the frequency and route of administration. PGE and PGA are similarly useful when administered in equivalent doses.

PGE PGA PGF and PGF B are useful whenever it is desired to inhibit platelet aggregation, to reduce the adhesive character of platelets, and to remove or prevent the formation of thrombi in mammals, including man, rabbits, and rats. For example, these compounds are useful in the treatment and prevention of myocardial infarcts, to treat and prevent post-operative thrombosis, to promote patency of vascular grafts following surgery, and to treat conditions such as atherosclerosis, arteriosclerosis, blood clotting defects due to lipemia, and other clinical conditions in which the underlying etiology is associated with lipid imbalance or hyperlipidemia. For these purposes, these compounds are administered systemically, e.g., intravenously, subcutaneously, intramuscularly, and in the form of sterile implants for prolonged action. For rapid response, especially in emergency situations, the intravenous route of administration is preferred. Doses in the range about 0.004 to about 20 mg. per. kg. of body weight per day are used, the exact dose depending on the age, weight, and condition of the patient or animal, and on the frequency and route of administration. PGE PGA PGF and PGF are similarly useful when administered in equivalent doses.

PGE- PGA PGFz and PGFZ are especially useful as additives to blood. blood products, blood substitutes. and other fluids which are used in artificial extracorporeal circulation and perfusion of isolated body portions. e.g.. limbs and organs, whether attached to the original body. detached and being preserved or prepared for transplant, or attached to a new body. During these circulations and perfusions, aggregated platelets tend to block the blood vessels and portions of the cir culation apparatus. This blocking is avoided by the presence of these compounds. For this purpose. the compound is added gradually or in single or multiple portions to the circulating blood, to the blood of the donor animal, to the perfused body portion, attached or detached. to the recipient, or to two or all of those at a total steady state dose of about .001 to 10 mg. per liter of circulating fluid. It is especially useful to use these compounds in laboratory animals, e.g.. cats, dogs, rabbits, monkeys. and rats, for these purposes in order to develop new methods and techniques for organ and limb transplants. PGEg, PGA PGFIinw and PGF are similarly useful when administered in equivalent doses.

PGE is extremely potent in causing stimulation of smooth muscle, and is also highly active in potentiating other known smooth muscle stimulators, for example, oxytocic agents, e.g., oxytocin. and the various ergot alkaloids including derivatives and analogs thereof. Therefore PGE is useful in place ofor in combination with less than usual amounts of these known smooth muscle stimulators. for example, to relieve the symptoms of paralytic ileus, to control or prevent atonic uterine bleeding after abortion or delivery, to aid in expulsion of the placenta, and during the puerperium. For these purposes. PGE is administered by intravenous infusion immediately after abortion or delivery at a dose in the range about 0.01 to about 50 g. per. kg. of body weight per minute until the desired effect is obtained. Subsequent doses are given by intravenous, subcutaneous. or intramuscular injection or infusion dur ing puerperium in the range 0.0l to 2 mg. per kg. of body weight per day. the exact dose depending on the age. weight. and condition of the patient or animal. PGE is similarly useful when administered in equ' '1- lent doses.

PGE PGA-g, and PGF- are useful as hypotensive agents to reduce blood pressure in mammals, including man. For this purpose, the compounds are administered by intravenous infusion at the rate about 0.01 to about 50 g. per kg. of body weight per minute or in single or multiple doses of about 25 to 500 g. per kg. of body weight total per day PGE PGA PGFB are similarly useful when administered in equivalent doses.

PGEQ. PGF, and PGF are useful in place of oxytocin to induce labor in pregnant animals, including man. cows, sheep. and pigs, at or near term. or in pregnant animals with intrauterine death of the fetus from about 20 weeks to term. For this purpose, the compound is infused intravenously at a dose 0.0] to 50 g. per kg. of body weight per minute until or near the ter mination of the second stage of labor. i.e., expulsion of the fetus. These compounds are especially useful when the female is one or more weeks post-mature and natural labor has not started. or 12 to 60 hours after the membranes have ruptured and natural labor has not yet started. PGE PGFfla, and PGF are similarly useful when administered in equivalent doses.

P01 PGF and PGE are useful for controlling the reproductive cycle in ovulating female marrimals, including humans and animals such as monkeys. rats. rabbits, dogs, cattle, and the like. For that purpose, PGF 0 is administered systemically at a dose level in the range 0.01 mg. to about 20 mg. per kg. of body weight of the female mammal, advantageously during a span of time starting approximately at the time of ovulation and ending approximately at the time of menses or just prior to menses. PGE PGF and PGF are similarly useful when administered in equivalent doses.

As mentioned above. PGE is a potent antagonist of epinephrine-induced mobilization of free fatty acids. For this reason, this compound is useful in experimental medicine for both in vitro and in vivo studies in mammals, including man, rabbits, and rats. intended to lead to the understanding, prevention, symptom alleviation. and cure of diseases involving abnormal lipid mobilization and high free fatty acid levels. e.g.. diabetes mellitus, vascular diseases. and hyperthyroidism. PGE is similarly useful when administered in equivalent doses.

PGE and PGB promote and accelerate the growth of epidermal cells and keratin in animals, including hu mans. useful domestic animals, pets, zoological specimens. and laboratory animals. For that reason. these compounds are useful to promote and accelerate heal ing of skin which has been damaged, for example, by burns. wounds, and abrasions. and after surgery. These compounds are also useful to promote and accelerate adherence and growth of skin autografts, especially small, deep (Davis) grafts which are intended to cover skinless areas by subsequent outward growth rather than initially, and to retard rejection of homografts. PGE and P68 are similarly useful when administered in equivalent doses.

For these purposes. these compounds as well as the compounds of the invention are preferably administered topically at or near the site where cell growth and keratin formation is desired, advantageously as an acrosol liquid or micronized powder spray, as an isotonic aqueous solution in the case of wet dressings. or as a lotion. cream. or ointment in combination with the usual pharmaceutically acceptable diluents. In some instances. for example, when there is substantial fluid loss as in the case of extensive burns or skin loss due to other causes, systemic administration is advantageous, for example. by intravenous injection or infusion, separate or in combination with the usual infusions of blood. plasma, or substitutes thereof. Alternative routes of administration are subcutaneous or intramuscular near the site, oral. sublingual, buccal. rectal. or vagina]. The exact dose depends on such factors as the route of administration. and the age, weight. and condition of the subject. Especially for topical use, these prostaglandins are useful in combination with antibiotics, for example. gentamycin. neomycin, polymyxin B. bacitracin. spectinomycin. and oxytetracycline. with other antibacterials, for example, mafenide hydrochloride. sulfadiazine. furazolium chloride. and nitrofurazone, and with corticoid steroids. for example, hydrocortisone. prednisolone. methylprednisolone, and fluprednisolone, each of these being used in the combina tion at the usual concentration suitable for its use alone.

Racemic PGE ,racemic PGF racemic PGF and racemic PGA each are useful for the purposes described above for the optically active compounds, but these racemic compounds offer the enormous advantage of being available in unlimited quantities at much lower cost, Raeemic PGB;, has like advantages and is useful for the same purposes as PGB Moreover, these racemic compounds are easier to purify since they are produced by chemical reactions rather than by extraction from biological materials or enzymatic reaction mixtures.

The PGEK, PGF PGA and P68 analogs and isomers cuase corresponding biological responses and are useful for corresponding purposes as PGE PGF PGA and PGB respectively.

To obtain the optimum combination of biological response specificity and potency, certain compounds within the scope of formulas Vllle and lXe are preferred. As discussed above, those formulas represent the PGE -type compounds and the PGF;; -type compounds. respectively. Referring to formulas Ville and lXe, when -CH -CH=CHACOOR .is attached in alpha configuration and, in the case of formula lXe, when the ring hydroxy is also attached in alpha configuration, the sterochemistry is typical of the known optically active F615;, and PGF According to this invention, preferred formula Ville and lXe compounds are those wherein CH -CH=CHACOOR and ring hydroxy are alpha, n is l and A is trimethylene, R is hydrogen and R; is hydrogen or methyl and R is ethyl. These preferred compounds exhibit superior biological response specificity and/or potency.

Certain compounds within the scope of formulas Vllle Xle are especially useful for one or more of the purposes stated above, because they have a substantially longer duration of activity than other compounds within the generic formulas, including PGE PGFnfl. PG Fgfl, PG A and PG B and because they can be administered orally, sublingually, intravaginally, buccally, or rectally, rather than by the usual intravenous, intramuscular, or subcutaneous injection or infusion as indicated above for the uses of these known prostaglandins and other compounds encompassed by formulas Vllle to Xle. These qualities are advantageous because they facilitate maintaining uniform levels of these compounds in the body with fewer, shorter, or smaller doses, and make possible self-administration by the patient With reference to formulas Vllle to Xle, these special compounds include those wherein A is (CH ),,Z, wherein h is zero, I, 2, or 3, and Z is ethylene substituted by l or 2 fluoro, methyl, or ethyl, or by one alkyl of 3 or 4 carbon atoms. These special compounds also include those wherein R is ethyl, propyl, isopropyl, isobutyl, tert-butyl, 3,3-difluorobutyl, 4,4-difluorobutyl, or 4,4,4-trifluorobutyl. These special compounds also include those wherein A is (CH ),,Z- as above defined, and R is ethyl, propyl, isopropyl, isobutyl, tertbutyl, 3.3-difluorobutyl, 4,4-difluorobutyl, or 4,4,4- trifluorobutyl. Especially preferred among these special compounds are those wherein R and R are both hydrogen.

in the case of Z. the divalent ethylene group, CH- .-CH is substituted on either or both carbon atoms, i.c.. alpha and/or beta to the carboxylate funcand similarly for ethyl, and for one fluoro and one methyl, one fluoro and one ethyl, and one methyl and one ethyl. Z is alternatively ethylene substituted on either carbon atom with propyl, isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl.

Although all of the special compounds just described have the special advantages of long duration and oral, sublingual intravaginal, and rectal routes of administration, there is a still more limited group of compounds encompassed by these formulas which have these qualities in a particularly high degree. Those are the compounds wherein A is CH -Z, i.e., wherein b in (CH ),,Z- is one, especially when Z is ethylene with one fluoro or methyl, with 2 fluoro or 2 methyl on the same carbon atoms, or with butyl, isobutyl, secbutyl, or tert-butyl on the carbon atoms alpha (adjacent) to the carboxylate function, the compounds wherein R2 is -C(CH3)3, -CH2- CF CH2CHF or -CH CF CH and the compounds wherein both A and R are both defined in these more limited ways.

Racemic PGE racemic PGFiiln racemic PGF3 racemic PGA racemic PGB and the other compounds encompassed by formulas Vllle and Xle, are used for the purposes described above in the free acid form, in ester form, or in pharmacologically acceptable v salt form. When the ester form is used, the ester is any of those within the above definition of R However, it is preferred that the ester be alkyl of one to four carbon atoms, inclusive. Of those alkyl, methyl and ethyl are especially preferred for optimum absorption of the compound by the body of experimental animal system.

Pharmacologically acceptable salts of these formula Vllle, lXe, Xe, and Xle compounds useful for the purposes described above are those with pharmacologically acceptable metal cations, ammonium, amine cations, or quaternary ammonium cations.

Especially preferred metal cations are those derived from the alkali metals, e.g., lithium, sodium and potassium, and from the alkaline earth metals, e.g., magnesium and calcium, although cationic forms of other metals, e.g.. aluminum, zinc, and iron, are within the scope of this invention.

Pharmacologically acceptable amine catons are those derived from primary, seconday, or tertiary amines. Examples of suitable amines are methylamine, dimethylamine, trimethylamine, ethylamine, dibutylamine. triisopropylamine, N-methylhexylamine, decylamine, dodecylamine, allylamine, crotylamine, cyclopentylamine, dicyclohexylamine, benzylamine, dibenzylamine, a-phenylcthylamine, B-phenylethylamine, ethylenediamine, diethylenetriamine, and the like aliphatic, cycloaliphatic, and araliphatic amines containing up to and including about 18 carbon atoms, as well as heterocyclic amines, e.g., piperidine, morpholine, pyrrolidine, piperazine, and lower-alkyl derivatives thereof, e.g., l-methylpiperidinc, 4- ethylmorpholine, l-isopropylpyrrolidine, 2 methylpyrrolidine, 1,4-dimethylpiperazine, 2- methylpiperidine, and the like, as well as amines containing water-solubilizing or hydrophilic groups, eg. mono-. di-, and triethanolamine. ethyldiethanolamine, N-butylethanolamine, 2-amino-lbutanol, 2-amino 2- ethyl-l,3-propanediol, 2-amino-2-methyl-l-propanol,

trislhydroxymethyl)aminornethane. N- phenylethanolamine, N-t p-tertamylphenyl )diethanolamine, galactaminc. N-methylglucamine, N- methylglucosamine, ephedrine, phenylephrine, epimerphrine, procaine. and the like.

Examples of suitable pharmaeologically acceptable quaternary ammonium cations are tetramethyl ammonium, tetramethylammonium, tetraethyl ammonium. benzyltrimethylammonium, phenyltriethylammonium, and the like.

As discussed above, the compounds of formulas Vllc to Xle are administered in various ways for various pur poses; e.g.. intravenously, intramuscularly, subcutane ously. orally, intravaginally. rectally, buccally, sublingually. topically, and in the form of sterile implants for prolonged action.

For intravenous injection or infusion. sterile aqueous isotonic solutions are preferred. For the purpose, it is preferred because of increased water solubility that R in the formula Vllle to Xle compound be hydrogen or a pharmacologically acceptable cation. For subcutane ous or intramuscular injection, sterile solutions or sus pensions of the acid. salt, or ester form in aqueous or non-aqueous media are used. Tablets, capsules, and liquid preparations such as syrups. elixers, and simple solutions, with the usual pharmaceutical carriers are used for oral or sublingual administration. For rectal or vaginal administration, suppositories prepared as known in the art are used. For tissue implants, a sterile tablet or silicone rubber capsule or other object containing or impregnated with the substance is used.

Racemic PGE racemic PGF racemic PGF B racemic PGA racemic PC113 and the other compounds encompassed by formulas Vlle, lXe, Xe, and Xle are produced by the reactions and procedures de scribed hereinafter. As intermediates there are produced the corresponding 5,6,1 7,] 8-dehydroprostaglandins Vllld. lXd, X11, and Xld which in the free acid or salt forms are useful also for the purposes given above. The cnantiomorphs of the V111, lX, X, and X1 compounds are formed either by resolution of the final product racemate or a racemic intermediate.

Racemic PGF racemic PGF B and the other PGF -type compounds encompassed by formula [X are prepared by carbonyl reduction of the corresponding PGE type compounds encompassed by formula Vlll. For example, carbonyl reduction of racemic PGE Vile, gives a mixture of racemic PGF ,lXea, and ra cemic PGF;,B lXeB. The corresponding 5,b.l7,l8- dehydro PGF;,-type compounds, lXd, are produced in a like manner from 5,6,17.18-dehydro-PGE -type compounds, Vllld. and by hydrogenation of the acetylenic bonds are converted to the corresponding PGF -type compounds. lXe.

These ring carbonyl reductions are carried out by methods known in the art for ring carbonyl reductions of known prostanoic acid derivatives. See. for example, Bergstrom et al.. Arkiv Kemi. i9, 563 1963), and Acta Chem. Scand. 16. 969 (1962), and British Pat. No. l,fl97,533. Any reducing agent is used which does not react with carbon-carbon double bonds or ester groups. Preferred reagents are lithium (tri-tert-butoxyl alumi num hydride and the metal borohydrides. especially sodium, potassium and zinc borohydrides. The mixtures ofalpha and beta hydroxy reduction products are separated into the individual alpha and beta isomers by methods known in the art for the separation of analo gous pairs of known isomeric prostanoic acid derivatives. See, for example, Bergstrom et 31.. cited above Granstrorn et al., J. Biol, Chem. 240. 457 1965), and Green et al., J. Lipid Research. 5, 117 (1964). Especially preferred as separation methods are partition chromatographic procedures, both normal and reversed phase, preparative thin layer chromatography, and countercurrent distribution procedures. They can be applied either before or after the hydrogenation of the acetylenic bonds.

Racemic PGA and the other PGA -type compounds encompassed by formula X are prepared by acidic de hydration of the corresponding PGE -type compounds encompassed by formula Vlll. For example, acidic dehydration of racemic PGE Vllle, gives racemic PGA Xe. The corresponding 5.6,l7,l8-dehydro-PGA -type compounds Xd, are produced in a like manner from 5.6,]7,l8-dehydro-PGE -type compounds, Vllld, and by hydrogenation of the acetylenic bonds are converted to PGA -typc compounds, Xe.

These acidic dehydrations are carried out by methods known in the art for acidic dehydrations of known prostanoic acid derivatives. See, for example, Pike et al., Proc. Nobel Symposium ll, Stockholm U966), lnterscience Publishers, New York, p. l6l (1967); and British Pat, No. 1,097,533. Aikanoic acids of 2 to 6 car bon atoms. inclusive. especially acetic acid, are preferred acids for this acidic dehydration. They can be applied either before or after the hydrogenation of the acetylenic bonds.

Racemic PGB and the other compounds encompassed by formula XIE are prepared by basic dchydra tion of the corresponding PGE -type compounds encompassed by formula Vllle or by contacting the corre' sponding PGA -type compounds encompassed by formula Xe with base, For example. both racemic PGE Ville, and racemic PGA Xe, give racemic PGB Xle, on treatment with base. Presumably the base first causes dehydration of the PGE to PGA and then causes the ring double bond of PGA;, to migrate to a new position. The corresponding 5,6,i7,l8-dehydro- PGB;,-type compounds, Xlrl, are produced in a like manner from 5,6,17,l8-dehydro-PGE Vllld, or 515.17,]S-dehydro-PGA -typC compounds, X0, and by hydrogenation ofthc acetylenic bonds are converted to PGB -type compounds. Xld.

These basic dehydrations and double bond migrations are carried out by methods known in the art for similar reactions of known prostanoic acid derivatives. See. for example, Bcrgstrorn et al., J. Biol. Chem. 238, 3555 (1963). The base is any whose aqueous solution has pH greater than l0. Preferred bases are the alkali metal hydroxides, A mixture of water and sufficient of a water-miscible alkanol to give a homogeneous reaction mixture is suitable as a reaction medium. The PGE;,-type or PGA;,-type compound is maintained in such a reaction medium until no further PGB type compound is formed. as shown by the characteristic ul traviolet light absorption for the PGB;,-type compound. They can be applied either before or after the hydrogenation of the acetylenic bonds.

These various transformations of the PG E type com pounds of formulas Vlllc to the PGF type, lXe. PGAg' type. XL. and PGB type. Xlc. compounds are shown in Chart A. wherein R,, R R R,. A, and are as defined above. The same transformation can be applied to the 5,ti.l7,li-dehydrtPGE -type compounds, Vllla'. as

3,883,575 13 14 shown in Chart A-l. If desired the 5,6,I7,18-dehydro- PGA -type compounds, Xd, can be converted to PGA type compounds, Xe, by hydrogenation by the procedures of step 8 and 8a infra.

Racemic PGE and the other PGE -type compounds encompassed by formula VIII are prepared by the multi-step processes outlined in Charts B, C, and D.

CHART A IXe reduction H H 0 c=c 0 c=c z A-C00R H2 A-coon acid c=c 0H H H C=C H H l H C C C HO /c cnHzn/ \R R C HZ R2 VI I I6 Xe base lbase H\ H o c=c CH2 A-COOR,

CHg-CEC-A-COOR;

cu EC-A-COOM and Step 7b CHg-CEC-A-COOR The bicyclic compound of formula Xll in Chart B is the initial reactant in these multi-step processes. It exists in two isomeric forms, exo and endo with respect to the attachment of the CR O moiety. It also exists in two isomeric forms with respect to the attachment of the tetrahydropyranyloxy group making in all four isomeric forms. Each of those isomers separately or mixtures thereof are used as reactants according to this invention to produce substantially the same final PGE type or 5,6,] 7,l8-dehydro-PGE -type product mixture.

In Belgian Pat. No. 702,477; reprinted in Farmdoc Complete Specifications Book 714, No. 30,905, page 3l3, Mar. 12. 1968, the reaction sequence leading to exo form of compound XII is as follows: The hydroxy wherein R is as defined above.

In the first step of the process (Chart B), the aidehyde group or keto group is transformed by the Wittig reaction to a moiety of the formula CR =CR C,,H- ,,-C CR which is in exo configuration relative to the bicycle ring structure, and is the same as shown in formula XIII. In step 2, the protective group is removed to regenerate the 3-hydroxy (XIV) which is then oxidized in step 3, for example, by the Jones reagent, to give the exo compound XV.

Separation of the cis-exo and trans-exo isomers of XV can be effected by the procedures described in said Belgian patent. However, as mentioned above, that separation is usually not necessary since the cis-trans mixture is useful as a reactant in the next process step.

The process described in said Belgian Pat. No. 702,477 for producing the exo form of bicyclic compound XII uses as an intermediate, the exo form of a bicyclo{3. l .U]-hexane substituted at 3 with a protected hydroxy, e.g tetrahydropyranyloxy and at 6 with an esterified carboxyl. When the corresponding endo compound is substituted for that exo intermediate, the Belgian patent process leads to the endo form of bicyclic compound XII. That endo intermediate used in the Belgian patent process has the formula:

CODCH XXVll Compound XXVII is prepared by reacting endobicyclo-[3.1.0lhex-Lene--carboxylic acid methyl ester with diborane in a mixture of tetrahydrofuran and diethyl ether, a reaction generally known in the art, to give endobicyclo[3 1.0lhexan-3-0l-6-carboxylic acid methyl ester which is then reacted with dihydropyran in the presence of a catalytic amount of POCI to give the desired compound. This is then used as described in said Belgian patent to produce the endo form of bicyclic compound XII.

Using this endo form of bicyclic compound XII as the starting material, steps 2 and 3 produce mixtures of endocis and enddtrans. These can be separated as described for the separation of exo-cis and exo-trans XV, but this separation is usually not necessary since, as mentioned above, the cis-trans mixture is useful as a reaetant in the next process step.

In the Wittig reaction, (Step I), the other starting compound is an organic chloride or bromide, or iodide of the formula XXVIII This can be prepared from the corresponding alcohol HOCHR -;C,,H ,,C I C--R XXIX by processes already known in the art, for example, by

reacting compound XXIX with triphenylphosphine and N-bromo-succinimide.

Acetylenic alcohols of formula XXIX are generally known in the art, for example, 3-pentyn-l-ol, 3-hexynl-ol, 4-hexyn-1-ol, 2-methyl-3-pentyn-l-ol, 2,3-dimethyl-4pentyn-1-ol, 6-octynl-ol, 6-nonynlol, 4-undecyn-l-ol, o-dodecyn-l-ol, S-tetradecyn-l-ol, and the like. Others where R;, is methyl, ethyl, propyl, butyl, or the isomers thereof can be made by reacting an acetylenic aldehyde of the formula with the appropriate Grignard reagent, BrMgR These acetylenic aldehydes can be made by oxidizing the corresponding alcohol, for example, those listed above, with a Jones reagent, Collins reagent, a Moffatt oxidation or the like. The aldehyde is then reacted with BrMgR to prepare acetylenic alcohols of formula XXIX. Compounds thus obtainable include 4-hexyn2- o1, 4-heptyn-2-ol, 5-heptyn2-ol, 3-methyl-4-hexynol, 3,4-dimethyl- S-hexyn-Z-ol, 7-nonyn-2-ol, 7-decyn- 2-01, 5-dodecyn-2-ol, 7-tridecyn2ol, 5-heptyn-3-ol, 5-octyn-3-ol, 6-octyn-3-0l, 8-undecyn-3-ol, o-tridecyn- 3-01, 8-tetradecyn-3-ol, and the like. Still other alkyn lols according to formula XXIX (R hydrogen) can be made by condensing an omega-alkyl-l-ol of the formula HOCH C H ,,C CH

xxxi

with an alkyl halide, Hal R using lithium and ammonia as the condensing agent; still others by condensing a protected halohydrin of the formula with a l-alkyn, HC 5 CR Again lithium and ammonia can be used as the condensing agent,

The protective tetrahydropyranyl group can then be removed by acid hydrolysis to form an acetylenic alcohol of formula XXIX. The latter process is particularly useful where R; is a halo substituted alkyl. The l-alkyn, HC I CR can be made by condensing acetylene with or sodium acetylide with an alkyl halide, R Hal where R is as given above.

The transformation of bicyclo-ketonc-olefin XXIII to glycol XXIV (Step 5, Chart B) is carried out by reacting olefin XXIII with a hydroxylation reagent. Hydrox' ylation reagents and procedures for this purpose are known in the art, See. for example, Gunstone, Advances in Organic Chemistry, Vol, 1, pp. lU3-l47, lnterscience Publishers, New York, NY. (I960). Various isomeric glycols are obtained depending on whether olefin XXIII is cis or trans and endo or exo, and on whether a cis or a trans hydroxylation reagent is used, Thus endo-cis olefin XXIII gives a mixture of two isomeric erythro glycols of formula XXIV with a cis hydroxylation agent, cg, potassium permanganate. The endo-cis olefins and the endo-trans olefins XXIII give similar mixtures of two threo isomers with cis and trans hydroxylation reagents, respectively. These various glycol mixtures are separated into individual isomers by silica gel chromatography. However, this separation is usually not necessary, since each isomeric erythro glycol and each isomeric threo glycol is useful as an intermediate according to this invention and the processes outlined in Charts B, C. and D to produce final products of formulas VIIIe and Xe, and then, according to Chart A, to produce the other final products of this invention. Thus the various isomeric glycol mixtures encompassed by formula XXIV produced from the various isomeric olefins encompassed by formula XXIII are all useful for these same purposes.

In step 4 the other starting material is a haloalkynoic ester of the formula HalCH -C CACOOR,

' XXXIII wherein Hal is chlorine, bromine, or iodine. In effecting this step any of the alkylation procedures known in the art to be useful for alkylating cyclic ketones with alkyl halides, especially haloalkynoic esters, can be used for the transformation of XV to XXIII. See, for example, the above mentioned Belgian Pat. No. 702,477 for procedues useful here and used there to carry out similar alkylations.

For this alkylation, it is preferred that Hal be bromo, or iodo. Any of the usual alkylation bases, e.g., alkali metal alkoxides, alkali metal amides, and alkali metal hydrides, are useful for this alkylation. Alkali metal al koxidcs are preferred, especially tert'alkoxides. Sodium and potassium are preferred alkali metals. Especially preferred is potassium tert-butoxide. Preferred diluents for this alkylation are tetrahydrofuran and 1,2 dimethoxyethane. Otherwise, procedures for produc ing and isolating the desired formula XXIII compound are within the skill of the art.

This alkylation procedure produces a mixture of alpha and beta alkylation products, i.e., a mixture of formula XXIII products wherein part has the CH C CA-COOR moiety attached in alpha configuration and wherein part has that moiety attached in beta configuration. When about one equivalent of base per equivalent of formula XV ketone is used, the alpha configuration usually predominates. Use of an excess of base and longer reaction times usually result in production of larger amounts of beta products. These alpha beta isomer mixtures are separated at this stage or at any subsequent stage in the multi-step processes shown in Charts B and D. Silica gel chromatography is preferred for this separation.

An alternative alkylation procedure is shown in steps 4a, 4b, and 4c. The alkylating agent XVII is reacted with the bicyclo-ketone-olefin XV by the alkylation procedure described above for step 4.

The alkylnting agent of formula XVII is prepared by the series of reactions shown in Chart C. The initial reactants, Br-ACH OH, are omega bromoalcohols which are known in the art or can be prepared by meth ods known in the art. For example, when A in the final product is to be trimethylene as it is in racemic PGE the necessary 4-bromobutanol is prepared by reacting tetrahydrofuran with hydrogen bromide.

To illustrate the availability of the other bromoglycols of formula XXI (Chart C consider the abovedescribed special compounds offormula VIIIe, wherein A is -(CH );,Z, wherein Z) is I), l, 2, or 3, and Z is ethylene substituted by one or Z-fIuoro, methyl, or ethyl, or by one alkyl of 3 or 4 carbon atoms. These ornega-bromoalcohols, Br(CH ),,ZCH.,OH, are prepared by starting with the appropriate succinic acid, HOOCZCOOH, all of which are known or easily accessible by known methods. These succinic acids are transformed to the corresponding anhydrides by known procedures. Each anhydride is then reacted with an alkanol, for example, methanol, to give the corresponding succinic acid half ester, e.g., HOOCZ-- COOCH;,. When Z is unsymmetrical, e.g., substituted with one fluoro, a mixture of isomeric half esters is obtained, HOOCZCOOCH and CH -OOC-Z- COOH, which is separated to give the desired isomer.

When it is desired that b is Br(CH )b-Z--CH OI I be zero, the succinic acid half ester is subjected to the Hunsdiecker reaction, thereby producing BrZ- COOCH which is reduced by lithium aluminum hydride to Br-ZCI-I OH. When b is to be I, the carboxyl group of the succinic acid half ester is changed to acid chloride with thionyl chloride, to aldehyde by the Rosenmund reduction, to alcohol with sodium borohydride. and to CH Br with PBr giving BR-CH- -Z-COOCH which is then reduced to Br-CH Z- CH OI-I with lithium aluminum hydride. When b is to be 2 or 3, the succinic acid half ester is subjected once or twice to the Arndt-Eistert reaction to produce HOO- C-CI-I Z-COOCH or HOCC-CH C- H -Z-COOCH:,, which is then subjected to the same series of reactions given above to give BrCH C- H Z-CH OH or BrCH CH CI-I ZCH OH.

Referring again to Chart C, the several process steps, XXI to XX, XX to XIX, XIX to XVIII, and XVIII to XVII are exemplified in Belgian Pat. Ser. No. 747,348, Sept. l4, I970, in the case wherein A is trimethylene. Those procedures are used when A is other than trimethylene and within the scope of A as defined above.

The transformation of alkylation product XVI to primary alcohol XXII (Chart B) is carried out by acid catalyzed hydrolysis of the tetrahydropyranyl ether XVI. Such hydrolysis of tetrahydropyranyl ethers is well known to those skilled in the art. Oxalic acid is especially preferred for this acid hydrolysis of XVI to XXII.

The oxidation of primary alcohol XXII to carboxylic acid XXIII (Chart B, R H) is carried out by oxidizing XXII with any oxidizing agent which will not also attack the acetylenic linkage in XXII. An especially useful reagent for this purpose is the Jones reagent, i.e., acidic chromic acid. See J. Chem. Soc. 39 1946). Ace tone is a suitable diluent for this purpose, and a slight excess of oxidant and temperatures at least as low as about 0 C., preferably about l0 to about "20 C. should be used. The oxidation proceeds rapidly and is usually complete in about 5 to about 30 minutes. Excess oxidant is destroyed, for example, by addition of a lower alkanol, advantageously isopropyl alcohol, and the aldehyde is isolated by conventional methods, for example, by extraction with a suitable solvent, e.g., diethyl ether. Other oxidizing agents can also be used. Examples are mixtures of chromium trioxide and pyridine or mixtures of dicyclohexylcarbodiimide and dimethyl sulfoxide. See, for example, I. Am. Chem. Soc. 87, 566I (I965).

The acid thus formed (compound XXIII, R, H) can then be esterified by procedures already known in the art for transforming carboxylic acids to esters. For example, a diazohydrocarbon, cg, diazomethane, advantageously in diethyl ether solution, is reacted with the acid to produce the ester, e.g., the methyl ester, by known procedures. When R, is ethyl substituted with 3-chloro, 2 or 3 bromo, or I, 2, or 3 iodo, the acid is reacted with the appropriate haloethanol, e.g., Bfifi-trichloroethanol, in the presence ofa carbodiimide, e.g., dicyclohexylcarbodiimide, and a base, e.g., pyridine. This mixture, advantageously with an inert diluent, e.g., dichloromethane, usually produces the desired haloethyl ester within several hours at about 25 C. The other esters within the scope of R are prepared by procedures known to the art.

In step 6 the vicinal hydroxy groups of the glycoi XXIV are modified by replacing the hydrogens with an alkanesulfonyl leaving-group, L, for example mesyl, containing up to and including 5 carbon atoms. Thus, the bis-alkanesulfonic acid esters XXV (Chart B) are prepared by reacting glycol XXIV with an alkylsulfonyl chloride or bromide, or with an alkanesulfonic acid anhydride. Alkylsulfonyl chlorides are preferred for this reaction. The reaction is carried out in the presence of a base to neutralize the by-product acid. Especially suitable bases are tertiary amines, e.g., dimethylaniline or pyridine. It is usually sufficient merely to mix the two reactants and the base, and maintain the mixture in the range to 25 C. for several hours. The formula XXV bis-alkanesulfonic acid esters are tn; r1 -olated by procedures known to the art.

The transformation in Chart D, Step 7a, of the modi fied glycol XXV to VIIId is carried out by reacting XXV with water in the range about 0 to about 60 C. The resulting product is racemic 5,6,l7,18-dehydro' PGE or an analog thereof. In making racemic 5,6,l7,I8-dehydro-PGE usually 25 C. is a suitable reaction temperature, the reaction then proceeding to completion in about to 10 hours. It is advantageous to have a homogenous reaction mixture. This is accomplished by adding sufficient of a water-soluble organic diluent which does not enter into the reaction. Acetone is a suitable diluent. The desired product is isolated by evaporation of excess water and diluent if one is used. The residue contains a mixture of formula VIIld isomers which differ in the configuration of the side chain hydroxy, that being either R or S. These are separated from by-products and from each other by silica gel chromatography. A usual by-product is the monosulfonic acid ester of formula XXVI (Chart D). This mono-sulfonic acid ester is esterified to the formula XXV bis-sulfonic acid ester in the same manner described above for the transformation of glycol XXIV to bis-ester XXV, and thus is recycled in step 7a.

For the transformation of bis-esters XXV to the formula VIIId products, it is preferred to use the bis-mesyl esters, i.e.. compounds XXV wherein L is mesyl.

In step 8a the aeetylenic linkages are hydrogenated to olcfinic linkages. A suitable method is to hydrogenate over a Lindlar catalyst in the presence of quinoline. The Lindlar catalyst is 5% paIladium-on-barium sulfate. Methanol or like inert solvent or diluent is used and the pressure is low, advantageously slightly above atmospheric and ordinarily not above about two atmospheres. The resulting products can be isolated by silica gel chromatography. If the starting material contains both the R and S epimers, the product Vllle will also contain the R and S epimers. These also can be separated by silica gel chromatography. As shown on Chart D, the hydrogenation of Vlllt] (or X11) leads to P6 type compounds depending on whether the acetylenic bonds of VIIld (or X11) are reduced to cis-'CH=CH.

The above described hydrogenation gives this type of reduction of the acetylenic bonds.

The transformation of the protected glycols XXV (Step 7b) to 5,6,l7,18-dehydro-PGA -type compounds (Xd) is carried out by heating the formula XXV bisestcr in the range 40 to [00 C. with a combination of water, a base characterized by its water solution having a pH 8 to l2, and sufficient inert water-soluble organic diluent to form a basic and substantially homogenous reaction mixture. A reaction time of I to l0 hours is usually used. Preferred bases are the water-soluble salts of carbonic acid, especially alkali metal bicarbonates, e.g., sodium bicarbonate. A suitable diluent is acetone. The products are isolated and separated as described above for step 7a and hydrogenated as in step 8a. The same mono-sulfonic acid esters XXVI observed as by products in step 7a are also observed in step 7b. Also, as in step 7b the bis-mesyl esters XXV are preferred. Also as in steps 7a and 8a, during production of Xd and Xe, alpha XXV gives alpha Xd and alpha Xe, beta XXV gives beta Xd and beta Xe, and in each case, alpha and beta Xd and Xe, a mixture of R and S isomers is obtained. These R and S isomer mixtures are separated by silica gel chromatography.

The configuration of the CH;(-

C-ACOOR moiety does not change during these transformations of Charts B and D. Also the configuration does not change in hydrogenation. There fore, when the CH C CACOOR, is attached initially in alpha configuration racemic 5,6,l7,l 8- dehydro-PGE typc, VIIId, PGE -type, VIIle, 5,6,17,l 8-dehydro-PGA -type, X0. and PGA;,-type, Xe, compounds are obtained. and when the moiety is attached in beta configuration, the S-isoforms are obtained.

Resolution of the final product racemates or the racemic intermediates are carried out by procedures known in the art. For example, when a final compound of formula VIIIe, IXe, Xe, or XLe is a free acid, the (II form (racemate) thereof is resolved into the d and l forms (the natural and unnatural configurations) by reacting said free acid by known general procedures with an optically active base, e.g., brucine or strychnine, to give a mixture of two diastereoisomers which are separated by known general procedures, e.g., fractional crystallization, to give the separate diastereoisomeric salts. The optically active acid of formula VIII to XI is then obtained by treatment of the salt with an acid by known general procedures. Alternatively, the free acid form of the intermediate dehydro compounds VIIId, IXd, Xd, or Xld is resolved into separate a and 1 forms and then esterified and transformed further to the corresponding optically active form of the final product VIIIe to Xle as described above.

Alternatively, glycol reactant XXIV, in exo or endo form, is transformed to a ketal with an optically active 1,2-glycol, e.g., D-(-)-2,3-butanediol, by reaction of said 1,2-glycol with the formula XXIV compound in the presence of a strong acid. e.g., p-toluenesulfonic acid. The resulting ketal is a mixture of diastereoisomers which is separated into the d and l diasterc oisomers, each of which is then hydrolyzed with an acid, e.g., oxalic acid, to the original keto compound, now in optically active form. These reactions involving optically active glycols for resolution purposes are generally known in the art. See, for example, Chem. Ind. I664 (I961) and J. Am. Chem. Soc. 84, 2938(1962). Dithiols may be used instead of glycols.

The novel PGE PGF PGA and PGB -type com- :ounds of formula Vllle to Xle wherein R is alkyl of me to 4 carbon atoms, inclusive, preferably methyl or :thyl, are preferred over the corresponding POE- GF PGAg, and PGB -type compounds in which R is iydrogen for the above-described pharmacological aurposes. For convenience the compounds of the inention where R is alkyl will be referred to as lS-alkyl lnalogs even though the number actually will be greater or less than 15 depending on whether the num- )61' of methylene groups in A is greater or less than hree.

These IS-alkyl prostaglandin analogs are surprisingly ll'ld unexpectedly more useful than the corresponding S-hydrogen compounds for the reason that they are ubstantially more specific with regard to potency in :ausing prostaglandin-like biological responses, and lave a substantially longer duration of biological activ ty. For that reason, fewer and smaller doses of these -alkyl prostaglandin analogs are needed to attain the lesired pharmacological results.

Although the abovementioned -alkyl compounds lf produced by the methods outlined above in Charts \D. the preferred methods are set forth in Charts E ind F as follows.

CHART E eta-(gunmen (Oxidation) CHg-Q-ACOOR;

a a 0H ln Chart E is shown the transformation of l5-alkyl PGF-type acids and alkyl esters to the corresponding 5 PGE-type acids and alkyl esters by oxidation. For this purpose, an oxidizing agent is used which selectively oxidizes secondary hydroxy groups to carbonyl groups in the presence of carbon-carbon double bonds. Formula lXu in Chart E includes optically active compounds as shown and racemic compounds of that formula and the mirror images thereof, and also the 15 epimers of both of those. i.e., wherein the configuration at C-l5 is R rather than S as shown. Also in Chart E, A, R R and R are as defined above. R is alkyl of one to 4 carbon atoms, and both Qs are ethynylene or cis-ethylene.

For the transformations of Chart E, the B-hydroxy isomers of reactant lXa are suitable starting materials 29 when the carboxyl side chain is alpha, although the corresponding a-hydroxy isomers are also useful for this purpose.

Oxidation reagents useful for the transformation set forth in Chart E are known to the art. An especially useful reagent for this purpose is the Jones reagent. i.e., acidified chromic acid. See J. Chem. Soc. 39 (i946). Acetone is a suitable diluent for this purpose, and a slight excess beyond the amount necessary to oxidize one of the secondary hydroxy groups of the formula lXa reactant is used. Reaction temperatures at least as low as about C. should be used. Preferred reaction temperatures are in the range to 5('J C. The oxidation proceeds rapidly and is usually complete in about 5 to minutes. The excess oxidant is destroyed, for example by addition of a lower alkanol. advantageously. isopropyl alcohol. and the formula Vllla PGE- type product is isolated by conventional methods.

Examples of other oxidation reagents useful for the Chart E transformations are silver carbonate on diatomite [Chem Commun. 1102 (1969)}. mixtures of chromium trioxide and pyridine [Tetrahedron Letters 3363 (i968. J. Am Chem. Soc. 75. 422 (i953). and Tetrahedron. 18. 1351 (1962)]. mixtures of sulfur trioxide in pyridine and dimethyl sulfoxide [1. Am. Chem. Soc. 89. 5505 (l967)]. and mixtures of dicyclohcx ylcarbodiimide and dimethyl sulfoxide (J. Am. Chem. Soc. 87. 566i (1965)].

The novel l5 alkyl P( :;a and PGF p type acids and esters of formula 1X11 are preferably prepared from the corresponding IS-hydrogcn compounds by the sequence of transformations shown in Chart F. wherein formulas IX. XXXVll. XXXVlll. lXa(S). and lXa(R) include optically active compounds as shown and racemic compounds of those formulas and the mirror im ages thereof. Also in Chart F. R is alkyl of one to 4 carbon atoms. inclusive. and A. R,. R R are as heretofore defined and Q is ethynylene or cisethylene. Also in Chart F. G is alkyl of one to 4 carbon atoms. inclusive. aralkyl of 7 to 12 carbon atoms. inclusive. phenyl. or phenyl substituted with one or 2 fluoro. chloro. or alkyl of one to 4 carbon atoms. inclusive. and R is alkyl or silyl of the formula Si(G) wherein G is as defined above. The various Gs of a SitG) moiety are alike or different. For example. a Si(G) Can be trimethylsilyl. dimethylphenylsilyl. or mcthylphenyl benzylsilyl. Examples ofalkyl of one to 4 carbon atoms. inclusive. are methyl. ethyl. propyl. isopropyl. butyl. isobutyl. sec-butyl. and tcrt-butyl. Examples of aralkyl of 7 to l2 carbon atoms. inclusive, are benzyl. phenethyl. a-phenylethyl. 3phenylpropyl. ot-naphthylmethyl. and Z-(B-naphthyl)-ethyl. Examples of phenyl substituted with one or 2 fluoro. chloro. or alkyl of one to 4 carbon atoms. inclusive. are p-chlorophenyl. mfluorophenyl. o-tolyl. 2.4-dichlorophenyl. p-tertbutylphenyl. 4-chloro-2-methylphenyl. and 2.4-dichloro3methylphenyl.

in Chart F. the final PGF and PGF;.B type prod ucts are those encompassed by formulas lXu(S) and lXa(R). respectively. where both Os arc cis-ethylene.

The heretofore-described acids and esters of formula lX are transformed to the corresponding intermediate IS-oxo acids and esters of formula XXXVII. by oxidation with reagents such as 2.3-dichloro5.6-dicyanol.4-bcn1oquinonc. activated manganese dioxide. or nickel peroxide [see Fieser ct al.. "Reagents for Organic Synthesis. John Wiley 8; Sons. lnc.. New York. N.Y.. pp. 215. 637. and 73] I. Alternatively. these oxidations are carried out by oxygenation in the presence of the lS-hydroxyprostaglandin dehydrogenase of swine lung [see Arkiv for Kemi 25. 293 1966)]. These reagents are used according to procedures known in the art. See. for example. J. Biol. Chem. 239. 4097 (i964).

The novel 5.6.l7.18-dehydro-PGF -type compounds of formula lXa are obtained by the borohydride reduction of the corresponding 5.6.17.l8dehydroPGE type compounds of formula Villa. Here again the numbcring is merely typical and will vary according to the values of A and )1.

Referring again to Chart F. the intermediate compounds of formula XXXVll are transformed to silyl de rivatives of formula XXXVI" by procedures known in the art. See. for example. Pierce. Silylation of Organic Compounds. Pierce Chemical Co.. Rockford. lll. (1968). Both hydroxy groups of the formula XXXVII reactants are thereby transformed to O-Si{G) moieties wherein G is as defined above. and sufficient of the silylating agent is used for that purpose accord ing to known procedures. When R is the formula XXXVII intermediate is hydrogen. the COOH moiety thereby defined is simultaneously transformed to COOSi-(G);.. additional silylating agent being used for this purpose. This latter transformation is aided by excess silylating agent and prolonged treatment. When R in formula XXXVI! is alkyl. then R in formula XXXVlll will also be alkyl. The necessary silylating agents for these transformations are known in the art or are prepared by methods known in the art. See. for example. Post. Siliconcs and Other Organic Silicon Compounds. Reinhold Publishing Corp. New York, NY. (I949).

Referring again to Chart F the intermediate silyl compounds of the formula XXXVlIl are transformed to the final compounds of formulas lXa(S) and lXa(R) by first reacting the silyl compound with a Grignard reagent of the formula R ,,MgHal wherein R is as defined above. and Hal is chloro. bromo. or iodo. For this purpose. it is preferred that Hal be bromo. This reaction is carried out by the usual procedure for Grignard reactions. using diethyl ether a reaction solvent and saturated aqueous ammonium chloride solution to hydrolyze the Grignard complex. The resulting disilyl or trisilyl tertiary alcohol is then hydrolyzed with water to remove the silyl groups. For this purpose. it is advantageous to use a mixture of water and sufficient ofa water-miscible solvent. cg. ethanol to give a homogeneous reaction mixture. The hydrolysis is usually complete in 2 to 6 hours at 25 C.. and is preferably carried out in an atmosphere of an inert gas. e.g.. nitrogen or argon.

The mixture of 15-5 and lS-R isomers obtained by this Grignard reaction and hydrolysis is separated by procedures known in the art for separating mixtures of prostanoic acid derivatives. for example. by chromatography on neutral silica gel. in some instances. the lower alkyl esters. especially the methyl esters of a pair of 158 and 15-R isomers are more readily separated by silica gel chromatography than are the corresponding acids. in those cases. it is advantageous to esterify the mixture of acids. separate the two esters. and then. if desired. saponify the esters by procedures known in the art and described herein.

The novel IS-alkyl PGA-type acids and esters of formula Xa are prepared from the IS-alkyl PGE compounds. Vllla, heretofore described. by dehydration as shown in Chart G. For this purpose, a dehydrating agent is used which removes the hydroxy group from the alicyclic ring in the presence ofa hydroxy group on a tertiary carbon atoms. Formula Vllla includes optically active compounds as shown and racemic compounds of that formula and the mirror images thereof, and also the lepimers of both of those, i.e., wherein the configuration at C1 5 is R or S and that of the carboxyl side chain is a or B,

Dehydration agents useful for the transformation to PGA -type compounds set forth in Chart G are known in the art. Any of the known substantially neutral dehydrating CHART G amount of a carbodiimide means one mole of the carbodiimide for each mole ofthe Formula-VIIla reactant, To ensure completeness of the reaction, it is advantageous to use an excess of the carbodiimide, i.e., 1,5 to 5 or even more equivalents of the carbodiimide.

The dehydration is advantageously carried out in the presence of an inert organic diluent which gives a homogeneous reaction mixture with respect to the Formula-Vlla reactant and the carbodiimide. Diethyl ether is a suitable diluent.

It is advantageous to carry out the dehydration in an atmosphere of an inert gas, e.g., nitrogen, helium, or argon.

The time required for the dehydration will depend in part on the reaction temperature. With the reaction temperature in the range 20 to 30C., the dehydration usually takes place in about 40 to hours.

The FormulaXa product is isolated by methods known in the art, e.g., filtration of the reaction mixture and evaporation of the filtrate. The product is then purified by methods known in the art, advantageously by chromatography on silica gel.

The conversion of F0rmula-VlIla and Formula-Xa compounds to Formula Xla compounds is effected with base as described above in connection with Charts A and A-l.

The formula VIII and X compounds produced according to the processes outlined in Charts B, C, and D and discussed above are all carboxylic acid esters, wherein R, is not hydrogen. Moreover, when these compounds are used to produce compounds of formulas IX and XI according to the processes outlined in Chart A and discussed above, corresponding R, esters are likely to be produced, especially in the case of the PGF compounds of formulas IX. For some of the uses described above, it is preferred that these formula VIII to XI compounds be in free acid form, or in salt form which requires the free acid as a starting material. It is also sometimes desirable to have the free acid or salt forms of the acetylenic compounds of the 5,6,l7,l8- dehydro-PGE -type (Vlld) and the 5,6,] 7,l8-dehydro- PGA -type (Xd) compounds, as well as the 5,6,l7,l8- dehydro-PGF -type (lXd) and 5,6,l 7,l8-dehydro- PGB -type (Xld) compounds and which are derivable therefrom by the processes outlined in Chart A-l, because these free acids and salt forms have properties like those of the corresponding hydrogenated (olefinic) compounds and are useful for the same purposes detailed above.

The formula lXe, XIe, lXd, and Xld R esters are easily hydrolyzed or saponified by the usual known procedures, especially when R, is alkyl of one to 4 carbon atoms, inclusive. Therefore it is preferred when the free acid form of compounds lXe, Xle, lXd, and Xld is desired, that R, by such alkyl, especially methyl or ethyl.

On the other hand, the formula VIIIe, Xe, VIld, and Xd products are difficult to hydrolyze or saponify without unwanted structural changes in the desired acids. There are two other procedures useful to make the free acid form of formula Ville, Xe, Vllld, and Xd products.

One of those procedures is applicable mainly in preparing the free acids from the corresponding alkyl esters wherein the alkyl group contains one to 8 carbon atoms, inclusive. That procedure comprises subjecting the alkyl ester corresponding to formula Ville, Xe, VI-

Ild, or Xd to the acylase enzyme system of a microorganism species of Subphylum 2 of Phylum Ill, and

thereafter isolating the acid. Especially preferred for this purpose are species of the orders Mucorales, Hypocreales, Moniliales, and Actinomycetales. Also especially preferred for this purpose are the species of the families Mucoraceae, Cunninghammellaceae, Nectreaceae, Moniliaceae, Dematiaceae, Tuberculariaceae, Actinomycetaceae, and Streptomycetaceae. Also especially preferred for this purpose are species of the genera Absidia, Circinella, Gongronella, Rhizopus, Cunninghamella, Calonectria, Aspergillus, Penicillium, Sporotrichum, Cladosporium, Fusarium, Nocardia, and Streptomyces.

Examples of microorganisms falling within the scope of those preferred orders, families, and genera are listed in US. Pat. No. 3,290,226 and details of the process are disclosed in German Offenlegunsschift No. 1,937,678, reprinted in Farmdoc Complete Specifications, Book No. 13, No. 6863R, Week R5, Mar. l8,

This enzymatic ester hydrolysis is carried out by shaking the formula Vllle, Xe, Vllld, or Xd alkyl ester in aqueous suspension with the enzyme contained in a culture of one of the above-mentioned microorganism species until the ester is hydrolyzed. A reaction temperature in the range 20 to 30C. is usually satisfactory. A reaction time of one to 20 hours is usually sufficient to obtain the desired hydrolysis. Esg'i' slon of air from the reaction mixture, for example, with argon or nitrogen is usually desirable.

The enzyme is obtained by harvest of cells from the culture, folllowed by washing and resuspension of the cells in water, and cell disintegration, for example, by stirring with glass beads or by sonic or ultrasonic vibrations. The entire aqueous disintegration mixture is used as a source of the enzyme. Alternatively and preferably, however, the cellular debris is removed by centrifugation or filtration, and the aqueous supernatant or filtrate is used.

In some cases, it is advantageous to grow the microorganism culture in the presence of an alkyl ester of an aliphatic acid, said acid containing lO to 20 carbon atoms, inclusive, and said alkyl containing one to 8 carbon atoms, inclusive, or to add such an ester to the culture and maintain the culture without additional growth for one to 24 hours before cell harvest. Thereby, the enzyme produced is sometimes made more effective in transforming the formula Vllle, Xe, Vllld, or Xd ester to the free acid. An example of a useful alkyl ester for this purpose is methyl oleate.

Although, as mentioned above, most of the R, esters encompassed by formulas Vllle, Xe, Vllld, and Xd are not easily hydrolyzed or saponified to the corresponding free acids, certain of those esters are transformed to free acids by another method. Those esters are the haloethyl esters wherein R is CH CCl They are transformed to free acids by treatment with zinc metal and an alkanoic acid of 2 to 6 carbon atoms, preferably acetic acid. Zinc dust is preferred as the physical form of the zinc. Mixing of the halo ethyl ester with the zinc dust at about 25C. for several hours usually causes substantially complete replacement of the haloethyl moiety of the formula Vllle, Xe. Vllld, or Xd ester with hydrogen. The free acid is then isolated from the reaction mixture by procedures known to the art. This procedure is also applicable to the production of the free acid form of the formula lXe, Xle, lXd, and Xld compounds from the corresponding haloethyl esters thereof.

As described above, the alkylation of cyclic ketone XV to ketone XXIII (Chart B) usually produces a mixture of alpha and beta alkylation products with respect to the CH C g CACOOR or the moiety. Also as described above, those two isomers lead to different final products, alpha leading to the PG -series and beta leading to the 8-iso-PG -series. If a compound in one or the other of those series is preferred, there are two methods for favoring production of the preferred final product.

One of those methods involves isomerization of the final product of formula Vllle or formula Vllld. Either the alpha isomer of formula Vllle or Vllld, or the beta isomer of formula Ville or Vllld is maintained in an inert liquid diluent in the range 0 to C. and in the presence of a base characterized by its water solution having a pH below about 10 until a substantial amount of the isomer has been isomerized to the other isomer, i.e., alpha to beta or beta to alpha. Preferred bases for this purpose are the alkali metal salts of carboxylic acids, especially alkanoic acids of 2 to 4 carbon atoms, e.g., sodium acetate. Examples of useful inert liquid dil uents are alkanols of one to 4 carbon atoms, e.g., ethanol. This reaction at about 25C. takes about one to about 20 days. Apparently an equilibrium is established. The mixtures of the two isomers, alpha and beta, are separated from the reaction mixture by known procedures, and then the two isomers are separated from each other by known procedures, for example, chromatography, recrystallization, or a combination of those. The less preferred isomer is then subjected to the same isomerization to produce more of the preferred isomer. In this manner, by repeated isomerizations and separations, substantially all of the less preferred isomer of the formula VIIIe or formula Vllld compound is transformed to more preferred isomer.

The second method for favoring production of a preferred final formula VIIle or formula Vllld isomer involves any one of the intermediates of formulas XVI, XXII, XXIII, XXIV, or XXV (Chart B). Either the alpha form or the beta form of one of those intermediates is transformed to a mixture of both isomers by maintaining one or the other isomer, alpha, or beta, in an inert liquid diluent in the presence of a base and in range 0 to C. until a substantial amount of the starting isomer has been isomerized to the other isomer. Preferred bases for this isomerization are alkali metal amides, alkali metal alkoxides, alkali metal hydrides, and triarylmethyl alkali metals. Especially preferred are alkali metal tert-alkoxides of 4 to 8 carbon atoms, e.g., potassium tert-butoxide. This reaction at about 25C. proceeds rapidly (one minute to several hours). Apparently an equilibrium mixture of both isomers is formed, starting with either isomer. The isomer mixtures in the equilibrium mixture thus obtained are isolated by known procedures, and then the two iso mers are separated from each other by known procedures, for example, chromatography. The less preferred isomer is then subjected to the same isomerization to produce more of the preferred isomer. In this manner, by repeated isomerizations and separations, substantially all of the less preferred isomer of any of these intermediates is transformed to the more preferred isomer.

The final formula Ville. lXe. Xe, and Xle compounds Part and Vllld, IXd. Xd. compounds prepared by the pro cesses of this invention. in free acid form. are transformed to pharmacologically acceptable salts by neutralization with appropriate amounts of the corre- 5 A mixture f n i y l l 1.0lhex-2-ene-6- Endobicyclo[ 3. l .0]hexan-3-ol-6-carboxylic acid methyl ester sponding inorganic or organic base, examples of which CaTbOXYliC acid hy CSIBY 3 g) and anhydrous correspond to the cations and amines listed above. diethyl ether 50 ml! is Stirred under nitrogen and These transformations are carried out by a variety of COOled 10 A one molar SOIUUOTI -l f dipmccdurcs known i h n to b generally f l f borane in tetrahydrofuran is added dropwise during 30 the p cparation of inorganic, i e meta] 1- ammonium minutes Whilfi keeping thC temperature bElOW 0C. The 1m amine id ddi i Salts, d quaternary ammoresulting mixture is then stirred and allowed to warm to nium salts. The choice of procedure depends in part 3500 during 3 hours- Evapmhhoh under reduced P upon the solubility characteristics of the particular salt Sure gives a residue WhiCh i5 di d in 650 ml. of anto be prepared. In the case of the inorganic salts. it is hydrous diethyl ether- The Solution 35 Cooled 0 0C. usually suitable to dissolve the acid in water containing and 3 normal aqueous Sodium hydl'oXlde Solution the stoichiometric amount of a hydroxide, carbonate. is added dropwise under nitrogen and with g or bicarbonate corresponding to the inorganic salt de- OUS Stirring during 15 minutes keeping thfi temperasired. For example, such use of sodium hydroxide, 50- {um at 00 to Next aquenus hydrogen P dium carbonate, or sodium bicarbonate gives a solution lde (94 ml) is added dropwise Wllh Stirring during 30 of the sodium salt. Evaporation of the water or addition minutes at 00 to 50 Theh- 500 of Saturated q ofa water-miscible solvent of moderate polarity. for exnus Sodium Chloride Solution 15 flddedand the diethyl ample, a lower alkanol or a lower alkanone. gives the ether layer is h The aqueous layer is Washed Solid inorganic; 1; if that f is desiredwith four 200 ml. portions of ethyl acetate, the wash- To produce an amine Salt. the formula VIlle, lXe. Xe, a being added to the diethyl ether y Whih is X18 \r'lud 1 1 4 or )(]d acid is dissolved in a Suitthen washed with saturated aqueous sodium chloride able solvent of ether moderate or low polarity. Exam- Soluuoh; dnedi h evaPorated to E 1 15 of a resiples of he former are ethanol acetone and ethyl due. This residue is distilled under reduced pressure to tate. Examples of the latter are diethyl ether and ben- 69 of a mixture the methyl esters of Endozene. At least a stoichiometric amount of the amine O l y l l add and endocorresponding to the desired cation is then added to hemhzol''carboxyhc llcldl pthat solution. If the resulting salt does not precipitate. Ema-(Mac at 05 mm it is usually obtained in solid form by addition ofa miscible diluent of low polarity or by evaporation. if the Part A-Z amine is relatively volatile, any excess can easily be re- 2 moved by evaporation. It is preferred to use stoichiometric amounts of the less volatile amines.

Salts wherein the cation is quaternary ammonium are The -0 n m'lXIUl'C 6 g] in d dCCOrding produced by mixing the formula Ville. lXe, Xe, Xle to Part A-l in 66 ml. of dihydropyran is stirred and Viild, lXd, Xd. or Xid acid with the stoichiometric 4O Cooled at during addition of 3 of yamount of he cg esponding quaternary ammonium ClI'OLlS Ethfil' saturated With hydrogen chloride. hydroxide in water solutiomfollowed by evaporation of The temperature of the mixture is p in [he the water range 20 to C. for one hour with cooling, and is The invention can be more fully understood by the thgh kept at 15 hours Evaporation E a T651 f u j exampies and preparations in which the pans due which is distilled under reduced pressure to give 66 are by weight and Solve, rat-ms arc by volume unless g. of a mixture of the methyl esters-tetrahydropyranyl Otherwise Specified esters of endob cyclolll.O]hexan-F-ol-6-carboxyl c Ali mmpemtures are in degrees centigrade acid and endobicyclol3.l.0]hexan-Z-ol--carboxylic NMR spectra are recorded on a Varian A-oO spectroand; 'P- 960-1040 at (H photometer on deuterochloroform solutions with tet- 5Q ramethylsilane as an internal standard (downfield). Part A-3 Mass 5 ectra are recorded on an Atlas CH-4 mass spectromgter with a TO-4 source (ionization voltage 70 Endo'fi'hydmxymemylblcyclo[3' l Ev) tetrahydropyranyl ether For convenience the formulas are given in the natural A solution of the mixture (69 g.) of products obconfiguration. it being understood. though. that the tained according to Part A-Z in 300 ml. of anhydrous compounds produced. unless otherwise specified. indiethyl ether is added dropwise during 45 minutes to a clude the cnantiomorphs. stirred and cooled mixture of lithium aluminum hydride (Zl g.) in L300 ml. of anhydrous diethyl ether Endo-bicyclo[3. l .0]hexan-3-ol-6-carboxy]ic acid methyl ester tetrahydropyranyl ether EXAMPLE l under nitroge. The resulting mixture is stirred 2 hours Racemic PGE methylester (XXXEX) at 25C., and is then cooled to 0 C. Ethyl acetate (71 H H ml.) is added. and the mixture is stirred l5 minutes.

\ Water (235 ml.) is then added. and the diethyl ether 0 (CH2 y COOCHS layer is separated. The water layer is washed twice with 5 diethyl ether and twice with ethyl acetate. A solution of Rochelle salts is added to the aqueous layer. which C 0HH H is then saturated with sodium chloride and extracted H twice with ethyl acetate All diethyl ether and ethyl ac- HO a/ \CHZCH3 ctute solutions are combined. washed with saturated XXiX aqueous sodium chloride solution. dried. and evaporated to give 61 g. of a mixture of the 3' tetrahydropyranyl ethers of endo-oh vdroxymethylbicicyl-l3.1.0]hexan-3-ol and endo-6- hydroxymethylbicyclo[ 3. l .0l-hexan-2-ol.

Part A-4 Endo-bieylo[ 3. l .0 ]hexan-3-o1-6carboxaldehyde 3-tetrahydropyranyl ether A solution of the mixture (34 g.) of products obtained according to Part A-3 in 1,000 ml. of acetone is cooled to -10 C. Jones reagent (75 ml. of a solution of 21 g. of chromic anhydride, 60 m1. of water, and 17 ml. of concentrated sulfuric acid). precooled to C., is added dropwise with stirring during 10 minutes at l0C. After 10 minutes of additional stirring at 10 C, isopropyl alcohol (35 m1.) is added during minutes, and stirring is continued for minutes. The reaction mixture is then poured into 8 1. of an ice and water mixture. The resulting mixture is extracted 6 times with dichloromcthane. The combined extracts are washed with aqueous sodium bicarbonate solution, dried, and evaporated to give 27 g. of a mixture of the tetrahydropyranyl ethers of endo-bieyclo[3.l .O]hexan-3-ol-6- carboxaldehyde (XL) and endo-bieyclo{3.l.Olhexan- 2-o1-6-carboxaldehyde.

Part B 3-Hexynyll -tripheny1phosphonium bromide To a solution of 130 g. (0.81 moles) of 1-bromo' hexB-yne in 250 ml. of benzene is added 236 g. (0.9 moles) of triphenylphosphine. The resulting solution is heated with stirring in a heating bath of 80C. for 24 hours. Stirring is continued at room temperature for 24 hours, then the reaction mixture is allowed to stand for 48 hours. An oil precipitated. The supernatant solution is decanted, the oil stirred in 200 m1. of benzene. The oil is again allowed to separate and the supernatant solution separated. The oil is dried under vacuum at room temperature, the oil solidifies while drying. The decanted solutions are combined and heated at 80C. bath temperature for 48 hours, workup as above re sulted in a second batch of solid material making a total yield of 210 g. of 3-hexynyl-l-triphenylphosphonium bromide.

Part C Endo-o-Hept l-en-4-ynyl-bieyclo[3.1.0]hexan-3-ol-3- tetrahydropyranyl ether (X L!) lHPO CHO 38 n-butyl lithium is added dropwise. When the addition was complete, stirring is continued for 20 minutes. Then a solution of 42 g. ofaldehyde XL in 150 ml. tetrahydrofuran is added dropwise with stirring over a period of 15 minutes.

The ice-methanol bath is replaced by a heating bath and the reaction mixture is heated at -70C. bath temperature for 3 hours. The reaction mixture is allowed to stand at room temperature overnight. The solvent is removed under reduced pressure. The residue is treated with 500 ml. benzene and filtered; the solid is washed with 500 ml. benzene, the benzene solutions combined and evaporated under reduced pressure. The resulting oil is triturated with 500 ml. of Skellysolve B (technical hexane), filtered and the resulting solution evaporated under reduced pressure to give 37 g. of a yellow oil. The oil is chromatographed using 1500 g. of silica gel. The column is developed with seven 1500 ml. portions of 1:1 benzene-Skellysolve seven 1500 ml. portions of benzene, five 1500 ml. portions of benzene containing 5% ethyl acetate, five 1500 ml. por tions of benzene containing 10% ethy acetate, and three 1500 m1. portions of ethyl acetate. Fractions 12-18 are combined to give a total of 12.9 g. oftetrahydropyranyl-ether XLl as a colorless oil. fractions 19-26 are combined to give a total of 13.5 g. of the corresponding alcohol XLII as a colorless oil.

Part D Endo-o-hept-l-en-tynyhbicyclol3.1.0]hexan-3-ol (XLIl) lll Part E Endo-b-hept-l-en-4-ynyl-bicyelo[3.1.0]hexan3-one (XLlll) XLlll A solution of 23.7 g. of alcohol XLll in 720 ml. of acetone is cooled to 5 to l0C. 48 ml. of Jones reagent is added dropwise over a period of 15 minutes maintaining a reaction temperature of0 to 5 C. When the addition is complete. stirring is continued for 10 minutes at -5 C. 34 ml. of isopropanol is added and stirring continued for 10 minutes. The green solution is poured into 5 liters of water and the aqueous solution 

1. AN OPTICALLY ACTIVE COMPOUND OF THE FORMULA:
 2. A compound according to claim 1 wherein R1 is hydrogen or alkyl of one to 4 carbon atoms, inclusive, or a pharmacologically acceptable salt thereof when R1 is hydrogen.
 3. An optically active compound according to claim 2 wherein the side-chain hydroxy is in S configuraTion.
 4. A compound according to claim 3 wherein R3 and R4 are hydrogen.
 5. A compound according to claim 4 wherein n is one.
 6. A compound according to claim 5 wherein A is trimethylene.
 7. A compound according to claim 6 wherein R2 is ethyl.
 8. 5,6,17,18-dehydro-PGB3, a compound according to claim 7 wherein R1 is hydrogen.
 9. A compound according to claim 3 wherein R3 is methyl and R4 is hydrogen.
 10. A compound according to claim 9 wherein n is one.
 11. A compound according to claim 10 wherein A is trimethylene.
 12. A compound according to claim 11 wherein R2 is ethyl.
 13. 5,6,17,18-dehydro-15-methyl-PGB3, a compound according to claim 12 wherein R1 is hydrogen.
 14. An optically active compound of the formula:
 15. An optically active compound according to claim 14 wherein the side-chain hydroxy is in S configuration, and wherein R1 is hydrogen or alkyl of 1 to 4 carbon atoms, inclusive, or a pharmacologically acceptable salt thereof when R1 is hydrogen.
 16. A compound according to claim 15 wherein R2 is ethyl, and R3 and R4 are both hydrogen.
 17. A compound according to claim 16 wherein b is
 1. 18. A compound according to claim 17 wherein Z is ethylene substituted with 2 fluoro on the carbon atom alpha to the carboxylate function.
 19. A compound according to claim 17 wherein Z is ethylene substituted with one methyl on the carbon atom beta to the carboxylate function.
 20. A compound according to claim 15 wherein R2 is ethyl, R3 is alkyl of 1 to 4 carbon atoms, inclusive, and R4 is hydrogen.
 21. A compound according to claim 20 wherein b is one.
 22. A compound according to claim 21 wherein Z is ethylene substituted with 2 fluoro on the carbon atom alpha to the carboxylate function.
 23. A compound according to claim 21 wherein Z is ethylene substituted with one methyl on the carbon atom beta to the carboxylate function. 